During the period following development or infliction of serious physical damage to the skin, by way of for example, severe burns, wounds, pressure ulcers, and the like, the injured area is extremely unstable physiologically; following such injury or trauma, the normal physiological processes of the area in question may be severely compromised. Disruption in the normal pattern of skin growth, blood flow, and immunity may all be impaired to some extent by the trauma to the region. The physician treating such damaged tissue must therefore be able to control and eventually reverse these undesirable effects, while at the same time stimulating the processes that are necessary to achieve healing of the area.
Because of the variety of different systems which may be adversely affected by such injury, it is difficult to find a single agent which will be effective in controlling the various sources of the problems. For example, one of the most severe difficulties encountered is the immediate colonization of the wound by a variety of different types of microbial species. Common invaders of a wound site are such known pathogens as Staphylococcus aureus, as well as a number of opportunistic pathogens, such as Escherichia coli or Pseudomonas aeruginosa. Various yeasts, particularly Candida albicans, may also be found at the wound. Although a number of antimicrobial agents for topical application are known, none has proven to be without some serious disadvantage. For example, silver sulfadiazine, the current antibacterial agent of choice is effective against gram-positive bacteria and gram-negative but many resistant strains have developed in the course of its use, particularly in the genus Pseudomonas. Similarly, the commonly used Betadine (povidone-iodine), although effective against both gram-positive and gram-negative bacteria, can be quite painful to the patient upon application, kills white cells in the wound, specifically polymorphonuclear cells, lymphocytes, monocytes, and macrophages, and may cause sensitization of an area already severely traumatized. Other known antibacterial agents may be hampered in their use by low diffusibility of the composition, or a range of activity that covers relatively few types of microbes; expense, as with substances such as the various silver salts, is also a factor to be considered.
Related to the invasion by microbes of the wound site is the generally decreased circulation which is also observed in many cases. For example, in decubitus or stasis ulcers, a cessation of blood flow may develop gradually, whereas an acute cessation of flow may occur in thermo-radiation and chemical burns. In either case the decrease in the rate of blood flow means a corresponding decrease in the provision to the cells of nutrients and oxygen. Thus deprivation in turn leads to necrosis of tissue in the poorly supplied region, which will be followed by the invasion of the unwanted bacteria and fungi. In order for healing to proceed, the damaged area must not only be rid of any lingering microbial infection, but also must have a restored blood flow, which will provide sufficient nutrient and oxygen supply to support a regeneration of the wounded region. In the ideal situation, the increased blood flow should also be accompanied by the formation of healthy granulation tissue. The latter is a layer of highly vascularized tissue, containing numerous fibroblasts and collagen and ground substance, which supports the normal wound healing processes of recollagenation and reepithelialization.
Another very critical aspect of the wound healing process is the initiation of wound closure. This is generally a two-stage process, comprising contraction and epidermal migration. Contraction is the process of bulk skin movement from the edges of the wound, while migration is the separation and movement of activated epidermal cells over the surface of the wound. Because contraction itself may lead to some scarring it is preferable to be able to speed healing in a manner which will increase the process of epidermal migration. The process of migration is characterized by a stimulation of mitosis in the epidermal cells, accompanied by movement across the wound site. The extent to which epidermal migration, and thus wound closure, can be promoted will also in some cases determine whether or not additional skin grafting is required to complete the healing of the wound.
It is thus evident that a large number of different factors must be controlled and/or stimulated in order to achieve thorough regeneration of the damaged tissue. Since the processes involved, and the mechanisms controlling them, are so diverse, it has proven difficult to pinpoint a single treatment composition or method which is capable of aiding and promoting most or all of the required processes simultaneously. As noted above with respect to the various antibacterial agents available, the majority of wound healing compositions available suffer from one or another deficiencies, whether it be in complexity of application, insufficient ability to control infection, irritation caused to the patient, limited range of protective activity, or expense (See for example D. Wise (ed.) Burn Wound Coverings, Vol. I Chap, I, p. 11-22, CRC Press, 1984).
It has now been surprisingly discovered that certain monosaccharides, when used either alone or in combination with many known wound treating compositions, may have the effect of providing added protection against microbial infection, enhancing the growth of granulation tissue, promoting the vascularization of the wound site, and/or stimulating the process of epidermal migration and wound closure. When the monosaccharides are used in combination with known compositions, the effects observed on wound healing are significantly and unexpectedly improved with respect to the above features. When used alone, the monosaccharides show a remarkable and unpredicted effect on control of bacterial infection on damaged skin. The monosaccharide fructose has proven to be most useful and successful in this regard.
Various monosaccharides have previously been known to be used for therapeutic purposes. For example, it is known to administer fructose intravenously to inhibit erythrocyte fragility during surgical extracorporeal circulation procedures (U.S. Pat. No. 4,448,771). Sorbose is also known (U.S. Pat. No. 4,390,523) to be used as a sugar substitute to inhibit acid formation by bacteria in the mouth, but it does not itself have an effect on bacterial growth. Oral administration of pure fructose is also known to control human stress response (U.S. Pat. No. 4,024,250). Bacteriostatic effects have also been attributed to irradiated glucose and fructose, but this effect is the apparent result of the peroxide compounds produced by the irradiation (Namike et al. Agr. Biol. Chem. 37(5): 989-998, 1973). The latter reference, in fact, shows normal bacterial growth in the presence of glucose and fructose. Various natural substances, such as honey or sugar (i.e., sucrose) have also been traditionally used as a type of folk-medicine for preventing infection. Thus, there has been no previous indication that monosaccharides would have any antibacterial effect either alone or in combination with other products for a topical wound healing preparation, and in fact, the monosaccharides show a more marked protective effect than disaccharides such as sucrose and lactose. As employed herein, the term wound is intended to apply to any skin or connective tissue trauma, such as thermal burns, pressure ulcers, ischemic ulcers, chemical and radiation burns, abcesses, fistulae, bone defects, malunion of fractures, vasculitis, tropical parasitic ulcers, leprosy ulcers, and acne or psoriasis lesions.